Hemiacetal Function Research Articles

Five Pairs of Enantiomer as Rearrangement Products from Secoiridoids in Gentiana macrophylla Pall.

Five racemates (1-5) were isolated from Gentiana macrophylla, in which 2-5 were successfully separated into four pairs of enantiomers (2a and 2b, 3a and 3b, 4a and 4b, and 5a and 5b), whereas the resolution of 1 failed due to the hemiacetal functionality at the stereogenic center. Using electronic circular dichrosim calculation, the relationship of the molecular rotation direction and the carbon R/S chirality was revealed, and each pair of enantiomer was identified as (-)-(S)-gentianmacrol B (2a) and (+)-(R)-gentianmacrol B (2b), (-)-(S)-8-methoxy-gentianol (3a) and (+)-(R)-8-methoxy-gentianol (3b), (+)-(S)-8-methyl-gentianadine (4a) and (-)-(R)-8-methyl-gentianadine (4b), and (-)-(S)-gentianol (5a) and (+)-(R)-gentianol (5b). Besides, these compounds could be divided into two series, 1-2 containing the benzene ring moiety and 3-5 containing the pyridine ring moiety. Considering that their molecular skeleton could not be generated from the classical biosynthesis pathway in plants, the plausible biosynthesis pathways of 1-5 were deduced to be transformed from secoiridoids in G. macrophylla. Due to the significant difference in the pharmacological effect for the optical factor, our research provided new diverse molecules for further optical activity studies in drug research.

New neo-clerodane diterpenes from Teucrium polium subsp. capitatum

Phytochemical investigation of a methanolic extract from the aerial parts of Teucrium polium subsp. capitatum afforded six acetoxylated neo-clerodane diterpenes, including 20-acetylauropolin and 6-acetylteucjaponin A, along with four previously undescribed congeners. The compounds were isolated by a combination of silica gel column chromatography and preparative HPLC-ESIMS. Their structures were determined by extensive NMR analysis, HRESIMS, and by comparison with literature data of related compounds. The absolute configuration of 20-acetylauropolin was confirmed by X-ray crystallographic diffraction analysis. Some of the isolated diterpenes possess structural features unusual in the class of neo-clerodane diterpenes, such as a rare C-20 hemiacetal function which forms an oxepane ring to C-7 of the trans-decalin core structure.

Hyaluronic Acid Surface Modified Liposomes Prepared via Orthogonal Aminoxy Coupling: Synthesis of Nontoxic Aminoxylipids Based on Symmetrically α-Branched Fatty Acids, Preparation of Liposomes by Microfluidic Mixing, and Targeting to Cancer Cells Expressing CD44.

New synthetic aminoxy lipids are designed and synthesized as building blocks for the formulation of functionalized nanoliposomes by microfluidization using a NanoAssemblr. Orthogonal binding of hyaluronic acid onto the outer surface of functionalized nanoliposomes via aminoxy coupling ( N-oxy ligation) is achieved at hemiacetal function of hyaluronic acid and the structure of hyaluronic acid-liposomes is visualized by transmission electron microscopy and cryotransmission electron microscopy. Observed structures are in a good correlation with data obtained by dynamic light scattering (size and ζ-potential). In vitro experiments on cell lines expressing CD44 receptors demonstrate selective internalization of fluorochrome-labeled hyaluronic acid-liposomes, while cells with down regulated CD44 receptor levels exhibit very low internalization of hyaluronic acid-liposomes. A method based on microfluidization mixing was developed for preparation of monodispersive unilamellar liposomes containing aminoxy lipids and orthogonal binding of hyaluronic acid onto the liposomal surface was demonstrated. These hyaluronic acid-liposomes represent a potentially new drug delivery platform for CD44-targeted anticancer drugs as well as for immunotherapeutics and vaccines.

Facile Chemoselective Strategy toward Capturing Sphingoid Bases by a Unique Glutaraldehyde-Functionalized Resin.

Sphingoid bases, which have a 2-amino-1,3-diol common functional group, are the structural backbone units of all sphingolipids. Recently, much attention has been focused on sphingoid bases because of their potentially beneficial bioactivities toward various cancer cells as well as their dietary interest. However, low abundance and the handling complexity caused by their amphiphilic character led to very limited research on them. Glutaraldehyde has two aldehyde groups, and it reacts rapidly with the 2-amino-1,3-diol functional group of sphingosine to give a tricyclic product. Immobilization of glutaraldehyde on a resin was successfully performed by organic synthesis, starting from trans-p-coumaric acid via eight steps. This approach suppresses the self-polymerization of glutaraldehyde, and addition of water to the developed resin causes the formation of cyclic double hemiacetal function, which avoids oxidation like a reducing sugar in nature and makes it stable even for up to 1 year incubation. The resin was applied to the solid-phase extracting experiment of free sphingosine from human serum at a concentration of 280 nM. Another extraction study of edible golden oyster mushrooms showed that the sphingoid base was selectively captured from complex natural extracts. These results demonstrate that the developed glutaraldehyde resin method is a highly selective method, and hence, the combination of it with the o-phthaldialdehyde HPLC method was confirmed as an efficient and sensitive method for analysis of sphingoid bases in biological samples.

3CAPS - a structural AP-site analogue as a tool to investigate DNA base excision repair.

Abasic sites (AP-sites) are frequent DNA lesions, arising by spontaneous base hydrolysis or as intermediates of base excision repair (BER). The hemiacetal at the anomeric centre renders them chemically reactive, which presents a challenge to biochemical and structural investigation. Chemically more stable AP-site analogues have been used to avoid spontaneous decay, but these do not fully recapitulate the features of natural AP–sites. With its 3′–phosphate replaced by methylene, the abasic site analogue 3CAPS was suggested to circumvent some of these limitations. Here, we evaluated the properties of 3CAPS in biochemical BER assays with mammalian proteins. 3CAPS-containing DNA substrates were processed by APE1, albeit with comparably poor efficiency. APE1-cleaved 3CAPS can be extended by DNA polymerase β but repaired only by strand displacement as the 5′–deoxyribophosphate (dRP) cannot be removed. DNA glycosylases physically and functionally interact with 3CAPS substrates, underlining its structural integrity and biochemical reactivity. The AP lyase activity of bifunctional DNA glycosylases (NTH1, NEIL1, FPG), however, was fully inhibited. Notably, 3CAPS-containing DNA also effectively inhibited the activity of bifunctional glycosylases on authentic substrates. Hence, the chemically stable 3CAPS with its preserved hemiacetal functionality is a potent tool for BER research and a potential inhibitor of bifunctional DNA glycosylases.

Diterpenoids from Scutellaria galericulata

Neo-clerodane diterpenoids have attracted interest for their varied biological activities. In continuation of our systematic studies on Scutellaria plants [1–3], we have now investigated S. galericulata L. The acetone extract of the aerial parts of S. galericulata was subjected to column chromatography to yield five compounds: 1–5. The IR spectrum of 3 showed signals for the hydroxyl group (3444 cm–1), oxirane (3050 cm–1), and ester groups (1733, 1712, 1651, 1276, 1256 cm–1), one of which is for a tigloyloxy moiety (1651 cm–1). The 1H NMR spectrum showed signals for an acetate  1.79 (3H, s) and tigloyloxy group H 7.10 (qq, H-3; 1.81 m, Me-4; 1.89 m, Me-5), as well as characteristic signals for the neo-clerodane structure (Me-17 at  0.84 d, J17,8 = 6.1 Hz, and Me-20 at  0.93 s) with a 4,18-oxirane ring (HA-18 2.44 d and HB-18 3.00 d, Jgem = 4.4 Hz) and a 19,2-hemiacetal function (H-19 6.78 s, H-2 4.23 m). The 1H NMR spectrum also showed signals for a 16,15--lactone (HA-15 3.94 ddd, HB-15 4.09 td, Jgem = 8.4 Hz, J15A,14A = 7.8 Hz, J15A,14BA = 4.7 Hz, J15B,14A = 7.8 Hz, J15B,14B =2.3 Hz). In addition to these groups, 3 possesses two esterified equatorial alcohols at C-6 (H-6 4.64 d, J6,7 = 10.9 Hz) and C-7 (H-7 5.19 dd, J7,6 = 10.9 Hz). On the basis of all the physical and spectroscopic data, compared with those described in the literature, compound 3 was established to be scutegalin D (16R and 16S epimers), because the 1H NMR spectrum also showed a series of double signals for the H-19 ( 6.78 s and 6.79 s) and CH3-17 group ( 0.84 d and 0.85 d). Moreover, the signals at  5.32 (0.5H, dd, J1 = 6.4, J2 = 2.7 Hz) and 5.15 (0.5H, t, J = 2.7 Hz) were assigned to the two C-16 epimeric forms of the 16,15-hemiacetal group [4]. Compounds 1, 2, 4, and 5 were neo-clerodanes with very similar structures. Their spectroscopic data showed the presence of a decalin ring system bearing one spiroepoxide substituent at C-4 (of C-1–C-10 fragment) and a furofuran system in the C-11–C-16 fragment ( 4.08 dd, H-11; 2.83 m, H-13; 5.63 d, H-16). The furofuran substructure was hexahydro in 1, 2, and 5 and tetradydro in 4 (3090, 1615 cm–1; and at  4.79 t, H-14; 6.43 t, H-15, J14,15 = 2.5 Hz, vinyl ether). DITERPENOIDS FROM Scutellaria galericulata

Potassium (1R,4R,5S,8S)-4,5,8-trihydroxy-3-oxo-2,6-dioxabicyclo[3.3.0]octane-4-sulfonate dihydrate

The title salt, K+·C6H7O9S−·2H2O, formed by reaction of dehydro-l-ascorbic acid with potassium hydrogen sulfite in water, crystallizes as colourless plates. The potassium ion is coordinated by eight O atoms arising from hy­droxy or sulfonate groups. The sulfonate group is bonded to the C atom neighbouring that of the lactone carbonyl group. As is commonly observed in crystalline l-ascorbic acid derivatives, the O atom of the primary hy­droxy group is linked to the second C atom from the lactone C atom, forming a hemi-acetal function, thereby creating a bicyclic system of two fused five-membered rings, both of which have envelope conformations with one of the shared C atoms as the flap. Addition of the sulfur nucleophile occurs from the less hindered face. One of the two independent lattice water mol­ecules has hydrogen bonds to sulfonate O atoms of two different anions and is the acceptor of bonds from hy­droxy groups of two further anions; the second lattice water mol­ecule donates to the carbonyl and a hy­droxy O atom in different anions, and accepts from a hy­droxy O atom in a further anion. Thus, through K—O coordination and hydrogen bonds, the potassium cations, sulfonate anions and water mol­ecules are linked in a three-dimensional network.

Interconvertible Eudesmanolides Containing a 6,12‐Hemiketal Function from Salvia castaneaDiels f. tomentosaStib.

AbstractTwo new eudesmanolide sesquiterpenoids containing a hemiacetal function, castanins G and H (1 and 2), were obtained as a pair of interconvertible isomers from the aerial parts of Salvia castanea Diels f. tomentosa Stib., and separated as their uninterconvertible acetates 3 and 4. Their structures were elucidated by unequivocal interpretation and comparative analysis of the NMR and MS data of the mixture 1/2 and of their acetates 3 and 4, respectively. The inhibitory activity of 3 and 4 toward MCF‐7, HeLa, and HepG2 cell lines was also evaluated.

Soyasaponin Bh, a Triterpene Saponin Containing a Unique Hemiacetal-Functional Five-Membered Ring fromGlycine max(Soybeans)

Soybeans (Glycine max L. Merill) and soy-based food products are major dietary sources of saponins. An oleanane triterpenoid saponin, soyasaponin Bh (1) containing a unique five-membered ring with a hemiacetal functionality together with seven known saponins were isolated from soybeans. Their structures were determined by chemical and spectroscopic analyses including HR-ESI-MS, 1D- and 2D-NMR. None of the isolated saponins showed any anti-cell proliferative activity in tumor cell lines. Soysaponin I showed a weak estrogenic effect in the yeast estrogen screen (YES) assay.

Glycinalside, a Triterpenoid Saponin Containing a Five-membered Ring with Novel Hemiacetal Functionality from Glycine max

Glycinalside, a Triterpenoid Saponin Containing a Five-membered Ring with Novel Hemiacetal Functionality from Glycine max

Identification of the Main Degradation Products of Patulin Generated Through Heat Detoxication Treatments

The chemical stability of patulin (PAT) was studied in model aqueous media at different temperatures and pH values in the presence and absence of sulfites. At pH 6, 50% was degraded within one hour at 100 degrees C. At lower pH the detoxication efficiency was strongly reduced. The compound 3-keto-5-hydroxy-pentanal was shown to be the main degradation product of patulin. As the hemiacetal function has to be transformed into an aldehyde before retroaldolization and lactone hydrolysis, sulfites, as expected, improved detoxication, especially at high pH. At pH 7 in the presence of 50 ppm sulfite, PAT was completely degraded within 3 h at 25 degrees C.

De facto molecular weight distributions of glucans by size-exclusion chromatography combined with mass/molar-detection of fluorescence labeled terminal hemiacetals

A major capability of polysaccharides in aqueous media is their tendency for aggregation and dynamic formation of supermolecular structures. Even extended dissolution processes will not eliminate these structures which dominate many analytical approaches, in particular absolute molecular weight determinations referring to light scattering data. An alternative approach for determination of de facto molecular weight for glucans with free terminal hemiacetal functionality (reducing end group) has been adjusted from carbohydrates for midrange and high-dp glucans: quantitative and stabilized labeling as aminopyridyl-derivatives (AP-glucans) and subsequent analysis of SEC-separated elution profiles based on simultaneously monitored mass and molar fractions by refractive index and fluorescence detection. SEC-DRI/FL of AP-glucans proved as an appropriate approach for determination of de facto molecular weight of constituting glucan molecules even in the presence of supermolecular structures for non-branched (pullulan), branched (dextran), narrow distributed and broad distributed and for mixes of compact and loose packed polymer coils (starch glucan hydrolizate).

Chemical basis for the antifeedant activity of natural hydroxamic acids and related compounds.

Natural hydroxamic acids and related compounds derived from the 1,4-benzoxazin-3-one structure show antifeedant activity against the aphid Rhopalosiphum padi. This antifeeding activity is based on the electrophilic character of the hydroxamic acid function, the opening of the hemiacetal function and the lipophilic character of the molecule. In addition, the antifeedant activity of the aqueous extracts of different tissues of Acanthus mollis (Acanthaceae) was determined. The activity observed is attributed to the presence of 2,4-dihydroxy-1,4-benzoxazin-3-one in the extracts.

Henry condensations with 4,6- O-benzylidenylated and non-protected d-glucose and l-fucose via DBU-catalysis

Mechanistic intermediates, and thermodynamically favored side products, in the Henry condensations of partially protected and non-protected pyranoses with a free anomeric hemiacetal function with nitromethane in various solvents for the kinetically controlled syntheses of C-glycopyranosides in the presence of DBU/molecular sieve catalyst system were identified.

Apotirucallane and Tirucallane triterpenoids from Luvunga sarmentosa.

The leaves of Luvunga sarmentosa yielded two new apotirucallane triterpenoids, 3-epi-skimmiarepin A (1) and 21,23-epoxy-7alpha,21-dihydroxyapotirucalla-14,24-dien-3-one (2), and a new tirucallane triterpene, 3-epi-flindissol (3). Because of a hemiacetal functionality at C-21, all compounds occurred as mixtures of 21-epimers. 3-epi-Skimmiarepin A (1) and 3-epi-flindissol (3) were oxidized to the corresponding gamma-lactones. The structures have been elucidated on the basis of mass and NMR spectroscopic methods.

Air oxidation of 17-hydroxycorticosteroids catalyzed by cupric acetate: formation of hemiacetal dimers

Hydrocortisone, cortexolone, hydrocortisone-17-butyrate, and budesonide were oxidized into α-ketoaldehydes by air exposure in the presence of Cu(OAc) 2. When free hydroxyl functions were present at position 17, hydrocortisone and cortexolone, the formed oxidation products, were identified as hemiacetal dimeric structures involving the free hydroxyl functions at position 17 and the newly formed aldehydes at position 21. Dimeric structures were established by using 1 H { 13 C } correlations (HSQC and HMBC) and 1 H 1 H correlations (COSY and ROESY). The hemiacetal function was further confirmed by reaction of the dimer formed from hydrocortisone with two equivalents of 3-methyl-2-benzotriazolinone hydrazine (MTBH), giving quantitatively two equivalents of the 3-methyl-2-benzotriazolinone hydrazone of 21-dehydrohydrocortisone. When no free hydroxyl function was present as in the case of hydrocortisone-17-butyrate and budesonide, the expected α-ketoaldehydes were obtained.

Homoisoflavonoids from Ophiopogon japonicus Ker-Gawler

From the ethyl acetate extract of the tuberous roots of Ophiopogon japonicus (Liliaceae) eight known and five new homoisoflavonoidal compounds were isolated. The new compounds are 5,7-dihydroxy-8-methoxy-6-methyl-3-(2′-hydroxy-4′-methoxybenzyl)chroman-4-one ( 1), 7-hydroxy-5,8-dimethoxy-6-methyl-3-(2′-hydroxy-4′-methoxybenzyl)chroman-4-one ( 2), 5,7-dihydroxy-6,8-dimethyl-3-(4′-hydroxy-3′-methoxybenzyl)chroman-4-one ( 3), 2,5,7-trihydroxy-6,8-dimethyl-3-(3′,4′-methylenedioxybenzyl)chroman-4-one ( 4) and 2,5,7-trihydroxy-6,8-dimethyl-3-(4′-methoxybenzyl)chroman-4-one ( 5). Their structures have been elucidated by mass and NMR spectroscopy. Compounds 4 and 5 are the first isolated homoisoflavonoids with a hemiacetal function at position 2.

Apotirucallane triterpenoids from Luvunga sarmentosa (Rutaceae)

The leaves of Luvunga sarmentosa (Bl.) Kurz. yielded eight apotirucallane triterpenoids named luvungins A–G, and 1α-acetoxyluvungin A. Characteristic of the structure are the seven-membered lactone-ring A, the α-hydroxyl or α-acetoxyl group at C-7 and an oxygen bridge in the side chain giving five-, six- or seven-membered rings, respectively. Because of a hemiacetal function at C-21, luvungin C occurred as a mixture of 21-epimers. The structures have been elucidated on the basis of MS and NMR spectral data. In addition, two known coumarins ostruthin (6-geranyl-7-hydroxycoumarin) and 8-geranyl-7-hydroxycoumarin as well as five known triterpenes friedelin, flindissone, melianone, niloticin and limonin were isolated.

Molecular basis of phospholipase A2 inhibition by petrosaspongiolide M.

Petrosaspongiolide M (PM) is an anti-inflammatory marine metabolite that displays a potent inhibitory activity toward group II and III secretory phospholipase A(2) (PLA(2)) enzymes. The details of the mechanism, which leads to a covalent adduct between PLA(2) and gamma-hydroxybutenolide-containing molecules such as PM, are still a matter of debate. In this paper the covalent binding of PM to bee venom PLA(2) has been investigated by mass spectrometry and molecular modeling. The mass increment observed for the PM-PLA(2) adduct is consistent with the formation of a Schiff base by reaction of a PLA(2) amino group with the hemiacetal function (masked aldehyde) at the C-25 atom of the PM gamma-hydroxybutenolide ring. Proteolysis of the modified PLA(2) by the endoprotease LysC followed by HPLC MS analysis allowed us to establish that the PLA(2) alpha-amino terminal group of the Ile-1 residue was the only covalent binding site for PM. The stoichiometry of the reaction between PM and PLA(2) was also monitored and results showed that even with excess inhibitor, the prevalent product is a 1:1 (inhibitor:enzyme) adduct, although a 2:1 adduct is present as a minor component. The 2:1 adduct was also characterized, which showed that the second site of reaction is located at the epsilon -amino group of the Lys-85 residue. Similar results in terms of the reaction profile, mass increments, and location of the PLA(2) binding site were obtained for manoalide, a paradigm for irreversible PLA(2) inhibitors, which suggests that the present results may be considered of more general interest within the field of anti-inflammatory sesterterpenes that contain the gamma-hydroxybutenolide pharmacophore. Finally, a 3D model, constrained by the above experimental results, was obtained by docking the inhibitor molecule into the PLA(2) binding site through AFFINITY calculations. The model provides an interesting insight into the PM-PLA(2) inhibition process and may prove useful in the design of new anti-inflammatory agents that target PLA(2) secretory enzymes.

Synthesis and comparison of the antiinflammatory activity of manoalide and cacospongionolide B analogues.

We have synthesized analogues of two naturally occurring antiinflammatory marine compounds, manoalide and cacospongionolide B, containing a pyranofuranone moiety which is considered the pharmacophoric group. The two compounds, and hence their analogues, differ in the presence or absence in the dihydropyran ring of an hemiacetal function which was considered essential to irreversibly inactivate phospholipase A2 (PLA2). The two series of compounds were tested for their inhibitory effects on secretory PLA2 belonging to the groups I, II, and III, and the activities were found to be similar in both series, irrespective of the presence or absence of the additional hemiacetal function. In addition, the PLA2 inhibitory activity increases with the increasing hydrophobic character of the side chain linked to the pyranofuranone moiety. The most active compounds, FCA and FMA, carry a farnesyl residue linked to the pyranofuranone substructure. The most potent PLA2 inhibitor, FMA, was tested in the mouse carrageenan paw edema at the oral dose of 10 mg/kg and showed an activity similar to the reference antiinflammatory drug, indomethacin.